19 Animal TSEs do not occur in all countries reporting sCJD and theincidence of sCJD is not lower in countries without animal TSEs. Mostnotably sCJD occurs in Australia and New Zealand where there have beenno reported cases of endogenous scrapie in sheep or goats. This fact hasbeen one argument supporting the view that scrapie is not a risk to humanhealth. (Will, 1991) Although new cases of TSE resulting from dietaryexposure to an animal TSE would not necessarily be recognised through achange in sCJD incidence. The occurrence of variant CJD (vCJD) in theUK is unlikely to have been recognised on this basis alone, since theannual non-familial CJD incidence (the sum of sCJD and vCJD) did not liesignificantly outside the normal annual variation for sCJD. (Bosque, 2002)720 However transmission of a French (classical) scrapie sample to C57Bl/6mice gave similar lesion profiles and Western blotting profiles to those forthe French sCJD and iatrogenic CJD (iCJD) samples used in the sameexperiment. (Lasmezas, 2001)21 Scrapie has also been transmitted to squirrel monkeys (Gibbs, 1980) andin a reverse experiment CJD was transmitted to two goats whichdeveloped a disease with clinical signs and pathology indistinguishablefrom scrapie. (Hadlow, 1980)Scenario 2(a). Endogenous atypical scrapie cases are found in countries thathave been thought to be free from animal TSEs.-------------------------------------------------------------------------------------------------------Q2: Would such a finding, in the absence of any other data linkingatypical scrapie to sCJD, affect the Committee’s assessment of thepotential risk?Scenario 2(b). Extensive surveillance, using tests that are known to detectatypical scrapie, is undertaken in non-European countries,such as USA, Australia and New Zealand, and no atypicalscrapie is found.

2. Transmission/ species barrier2.1 Transmission of atypical scrapie25 When atypical scrapie was first reported it was not clear whether this wasa TSE i.e. transmissible or if it was a neurodegenerative condition withincreased prion protein. Work to assess transmissibility was firstundertaken where there would be little or no species barrier.26 Limited work has been published to date on the transmissibility of atypicalscrapie. Tg338 mice which overexpress the ovine VRQ prion protein, witha level in the brain of 8-10 times that in sheep, were inoculated intracerebrally(i.c.) with brain samples from 2 Norwegian Nor98 cases plus 10French cases classified as ‘discordant’ in the French surveillance program(9 sheep (including 3 of the ARR/ARR genotype) and 1 goat). All micewent down with clinical disease 200-300 days post inoculation (dpi).Titration of mouse-passaged Nor98 in Tg338 had given an i.c. ID50 ofapproximately 1ng brain. Whereas inoculation of Nor98 into inbred mouselines (RIII, C57Bl and VM) had failed to transmit after 850 dpi. However,shortened incubation periods in Tg338 compared to inbred lines had alsobeen observed with classical scrapie. (Le Dur, 2005) A similarlyoverexpressing VRQ transgenic mouse line, Tg301, gave an incubationperiod of 73 days for classical scrapie as compared to 423 for RIII mice.(Vilotte, 2001).27 The Nor98 and the sheep and goat discordant samples transmitted toTg338 all resulted in a unique TSE, different from some 50 classicalscrapie isolates previously transmitted to these mice. The Nor98proteinase K resistant prion protein (PrPres) Western blot profile wasmaintained in the brains of the Tg338 mice and was also detectable in allthe mice inoculated with the French samples. All other analyses, includinglesion profiling, also gave identical results to those from the Nor98samples. However no abnormal prion protein (PrPsc) was detected in thecerebellum of the Tg338 mice for any sample in contrast with the highcerebellar levels found in sheep with atypical scrapie.28 Defra has funded research projects to investigate the transmissibility of Ukatypical scrapie isolates to wild type and mice carrying the VRQ and ARQalleles of sheep PrP as transgenes (see below). results to date indicatethat UK isolates have a similar transmissibility to Tg338 mice as Nor98 andNor98-like isolates from other European countries.29 Sheep have been challenged i.c. with atypical scrapie in another Defrafunded project. In December 2005 one sheep came down with clinicaldisease (at 378 dpi).

snip...

2.2 Transgenic mice expressing the human prion protein (PrP) gene30 Having established the transmissibility of atypical scrapie to ovine PrPtransgenic mice the important question for human risk is the relativetransmissibility to mice expressing the human PrP gene. transgenic mousemodels carrying various alleles of human PRNP have been developed andtheir response to challenges with BSE, vCJD, sCJD CWD and scrapiehave been described.31 Tg35 and Tg45 mice expressing the human 129 M PrP gene werechallenged with BSE and vCJD prions which transmitted disease resultingin neuropathology and Western blotting profiles of the source diseases.However Tg152 mice expressing the human 129 V PrP gene showeddecreased transmission, as might be expected from the known humanresults, but gave a Western blotting pattern for PrPres and a weak, diffusedisease-associated prion protein (PrPd) distribution in the brain thatdiffered from that for BSE, vCJD or Tg35/45 mice. (Wadsworth, 2004)Further different results were found, with four distinct phenotypes, whenheterozygous 129 MV mice were bred from Tg45 and Tg152 andinoculated with vCJD and BSE, providing information for comparison withhuman CJD. (Asante, 2006)32 The potential susceptibility of humans to CWD has also been investigatedin transgenic mice. Mice expressing the human 129 M prion protein at 1-or 2-fold that in wild-type mice, or the elk 132 M prion protein (at 2-fold)were inoculated with brain tissue from elk CWD or human sCJD cases.CWD transmitted to all but one of the elk transgenic mice by 178 dpi,whereas the human transgenic mice survived at least 756 or 657 (two11different mouse lines) with no detectable PrPd. Control inoculations ofsCJD produced disease after an average of 263 or 226 days in the miceexpressing the human protein. (Kong, 2005) Similar results of positivetransmission were obtained when a more extensive range of CWD casesfrom elk, mule deer and white-tailed deer were inoculated into transgenicmice overexpressing the prion protein gene of each cervid species and ofno transmission of these CWD cases to transgenic mice overexpressingthe human, ovine or bovine prion proteins. (Tamguney, 2006)33 Mice which overexpress the prion protein transgene be more susceptibleto the inoculated disease as they produce abnormally high levels of thetransgenic normal cellular prion protein (PrPc). As an alternative mice havebeen developed where the mouse PrP gene has been directly replaced bythe human (or other) gene, such that protein expression is regulated in thenormal way, and they are therefore more likely to respond to any naturalchanges that may occur as the result of infection.34 Such mice with the human 129 MM, VV and MV genotypes have beenproduced. Transmission of vCJD and BSE to these mice by i.c. inoculationwas analysed in comparison to the identical mice expressing the bovinegene. The human gene targeted mice were susceptible to vCJD(measured by clinical disease or detectable PrPd) with 11/17 of the MM,11/16 MV and 1/16 VV showing positive transmission. Inoculation of BSEgave no positive transmission results for groups of 18, 23 and 22 humantransgenic MM, MV and VV mice respectively, whereas all 22 bovinetransgenics were susceptible. (Bishop, 2006) These results are interpretedas suggesting a significant species barrier for humans to BSE and a muchlower barrier for secondary transmission of vCJD between humans, with allgenotypes being susceptible to varying degrees. A lengthy pre-clinicalphase for vCJD is also predicted. Detailed analysis of these mice has alsoprovided information on the possible neuropathological and biochemicalcharacteristics that might result from human to human transmission ofvCJD.

2.3 Non-human primates36 In the US a large number of samples from human TSE cases from 1963-1993 have been inoculated into a range of non-human primate speciesand the resulting disease studied. (Brown, 1994)37 A limited number of experiments have been carried out to inoculate nonhumanprimates with animal TSEs. Two adult squirrel monkeys inoculatedi.c. with brain from a mule deer with clinical CWD came down with clinicaldisease and were euthanized at 31 and 34 months post inoculation.13Histology showed typical spongiform change and PrPres could be detectedby Western blotting. (Marsh, 2005) Historically squirrel monkeys havebeen inoculated with a number of other TSEs which have produceddisease with relatively short incubation periods – transmissible minkencephalopathy (TME), scrapie, sCJD and kuru.38 A series of experiments have been carried out in which cynamolgusmacaques were inoculated i.c. and intratonsilar with BSE, sCJD, iCJD(growth hormone) and vCJD and oral BSE in which the resulting diseasesclosely mimicked these diseases in humans. Detailed studies of theresulting tissue distribution (Herzog, 2005) and a comparison of theneuropathology and PrPres profile with that found in humans show thatBSE is the agent responsible for UK vCJD and French vCJD and thatthese differ from the iCJD and sCJD cases tested. (Lasmezas, 2001)Results of studies of two macaques, which are all of the 129 MMgenotype, fed 5g of BSE infected bovine brain were used to estimate thehuman oral ID50 as being in the range 150 – 1,500g. One of the twomacaques having developed disease at 60 months, but with the othershowing no clinical signs at 76 months, including a negative tonsil biopsyat 72 months. These results were compared with those for cattle and RIIImice to provide the estimate. (Lasmezas, 2005)39 A range of TSEs – 2 pooled sCJD cases, 3 pooled vCJD cases andleukocytes from chimpanzee-passaged Gerstmann-Straussler-Scheinkerdisease (GSS) were inoculated i.c. into squirrel monkeys at two dilutionsand the resulting clinical signs, neuropathology and biochemistry wereanalysed. (Williams, 2007) In particular a systematic behavioural studywas undertaken, in which the behaviours were noted to differ from thosereported for cynamolgus macaques by Lasmezas et al.40 At the time of writing it is not known if experiments to inoculate atypicalscrapie into non-human primates are underway.

snip...

55 Whilst the incidence of sCJD shows natural statistical variation from oneyear to another recent increases have been noted in a number ofcountries, but are usually attributed to improved diagnosis in the absenceof any other epidemiological evidence. However in 2001 and the firstquarter of 2002 significant increases were reported for Switzerland raisingthe incidence to 2.7 and 3.9 per million, respectively. Cases were fullyinvestigated but no explanation for this increase was found, which wasconsidered unlikely to be due to chance fluctuation or ascertainment bias.(Glatzel, 2002) sCJD incidence remained at a level averaging 2.42 casesper million from 2001-2004, but decreased to previous levels in 2005.(EUROCJD)56 A number of sub-types of sCJD have been recognised based on PrP 129genotype and the clinical, pathological and biochemical features of thedisease which may relate to distinct human prion strains. Classification canbe complicated in some cases by the presence of more than one PrPscsub-type in the brain.(Parchi, 1999b; Hill, 2003; Schoch, 2006: Wadsworth,2007)57 In addition new cases of sCJD have occurred that appear to lie outside thenormal disease spectrum, including a sporadic disease resembling FFI.(Yamamoto, 2003; Zanusso, 2007; Mastrianni, 1999; Parchi, 1999a andreviewed in Wadsworth, 2007)58 In the absence of any definitive data on the aetiology of sCJD it is normallyassumed to arise from an age-related somatic cell mutation in the PRNPgene, a spontaneous conversion of PrPc into PrPsc or an imbalance in the18normal in vivo regulation of the synthesis and degradation of normal PrPprotein and/or the abnormal form. (Reviewed in Belay, 1999; Johnson,2005)59 However a number of polymorphisms have now been associated withincreased or decreased susceptibility to sCJD. The best known is theencoding of methionine or valine at codon 129, but polymorphisms havealso been found upstream of PRNP Exon 1 (Mead, 2001) and in a largeGerman case control study in the 5’ UTR of the PRNP gene severalpolymorphisms have been identified which act independently of codon129. (Vollmert, 2006) Alternatively another polymorphism in the regulatoryregion of PRNP has been associated with susceptibility in codon 129 MVheterozygotes. (Bratosiewicz-Wasik, 2007)60 Case control studies for surgery or treatment with blood/products have notshown any definite links. (Brown, 1987; Van Duijn, 1998) Some links withsurgery were shown in a study by Ward et al (2002) when using telephonerecruited controls rather than hospital controls, but results showed anegative risk from surgery, such as neurological, tonsillar orappendectomies for which an association might be anticipated, and apositive risk with gynaecological or gastrointestinal surgery. This supportsthe possibility that some cases classified as sCJD may have an iatrogenicorigin.61 In view of the unknown human health implications of atypical scrapie andthe possible altered clinical phenotype of vCJD in individuals of non-MMgenotype, the UK Chief Medical Officers recently sent a letter toneurologists to remind them to remain vigilant and refer unusualneurological cases through the established national arrangements forreferral and reporting of suspect cases of human prion disease.Conclusions62 It is obviously extremely difficult to establish a definitive link between ananimal and a human TSE. “But a rare disease may be caused by rareexposure to its causative agent, especially if the rate of infection isinefficient”. (Brown, 1987)

http://www.seac.gov.uk/papers/97-3.pdf

WHAT DID DID 16 YEAR OLD VICKEY RIMMER HAVE ??? SPORADIC CJD

WHAT DID ALL THOSE FARMERS AND THERE WIVES HAVE ??? SPORADIC CJD

POLICY IN CONFIDENCE: CJD IN FARMER WITH BSE COW

LIKELY TO ATRACT MEDIA ATTENTION

http://www.bseinquiry.gov.uk/files/yb/1992/08/13002001.pdf

http://www.bseinquiry.gov.uk/files/yb/1992/08/21002001.pdf

http://www.bseinquiry.gov.uk/files/yb/1992/08/21005001.pdf

CONFIRMED CJD IN FARMER WITH BSE COW

line to take, sporadic CJD

http://www.bseinquiry.gov.uk/files/yb/1992/10/22004001.pdf

http://www.bseinquiry.gov.uk/files/yb/1992/10/22005001.pdf

http://www.bseinquiry.gov.uk/files/yb/1992/10/22001001.pdf

http://www.bseinquiry.gov.uk/files/yb/1992/11/05002001.pdf

http://www.bseinquiry.gov.uk/files/yb/1992/11/05003001.pdf

SECOND CASE CJD IN DAIRY FARMER

http://www.bseinquiry.gov.uk/files/yb/1993/00/00001001.pdf

CJD IN AN INDIVIDUAL OCCUPATIONALLY EXPOSED TO BSE

ii. on page 2 the sentence ''He had drunk pooled milk from the herd which included that from the affected animal'' will mislead the uninformed. It needs to be made clear that milk from a cow which is suspected to be affected with BSE cannot be drunk or added to the bulk milk produced by the rest of the herd.

iii. in the final paragraph I suggest that the phrase ''and a causal link with BSE is at most conjectural'' BE DELETED: the first paragraph of the sentence would then stand as a clear statement that the CJD case was likely to have been a CHANCE PHENOMENON.

http://www.bseinquiry.gov.uk/files/yb/1993/02/15003001.pdf

''DH is aware of a second case of CJD in a dairy farmer who has had BSE in his herd. We cannot comment on the details of the case, but we know of nothing to suggest this is anthing other than a sporadic case of CJD. .........

http://www.bseinquiry.gov.uk/files/yb/1993/07/12001001.pdf

IF PRESSED:

The numbers concerned are very small, and it is not possible to draw any conclusions from such small numbers. This issue is being considered by the Government's expert advisers....

http://www.bseinquiry.gov.uk/files/yb/1993/07/12002001.pdf

THE FARMER IS THOUGHT TO HAVE HAD AT LEAST TWO CASES OF BSE IN HIS HERD, which were diagnosed in 1992. The farmer is reported to have asssisted in calving and to have drunk milk from his herd. This does not suggest that this is anything other than a sporadic case of CJD. ...

http://www.bseinquiry.gov.uk/files/yb/1993/07/12003001.pdf

CONFIDENTIAL

CONFIRMED CASE OF CJD IN DAIRY FARMER

http://www.bseinquiry.gov.uk/files/yb/1993/07/14003001.pdf

3. Neither Dr Will nor the CJD surveillance unit intend to disclose the existence of this case or make any comment at present unless it attracts media attention.

snip...

HUMAN CASE DETAILS CONFIDENTIAL

snip...

6. CJD IN FARMERS

The second annual report on CJD surveillance in the UK, which is about to be published, gives occupational history details of 29 definite and probable CJD cases recorded in people who had a history of employment at any time in particular occupational groups of potential significance for the occurrence of the disease. The 29 cases were amongst 95 diagnosed over a 3 year period: the other 66 cases did not fall into such occupational groups.

1. The article in the Daily Mail of 12 August again raises the question of a CAUSATIVE LINK BETWEEN BSE AND CJD. This follows the death of a second farmer from CJD...

snip...

I am, however, concerned about how DH and MAFF would respont to public concern generated if there are further CJD cases among farmers.

snip...

4. Unwelcome, though it maybe to the Tyrrell Committee, I think they must be asked at their next meeting to give further thought to what they might advise the Department and MAFF if ANOTHER FARMER (or TWO) DEVELOPS CJD. OR, if a butcher or abattoir worker develops the disease.

5. Although the Committee were given plenty of advance warning about the second farmer, they may NOT BE SO FORTUNATE NEXT TIME ROUND. Some Contingency planning on the Committee's response to a further case of CJD in a farmer seems essential. At the same time the Committee should consider if there is SPECIAL RISK TO FARMERS, FOR EXAMPLE THEIR HISTORICAL HABIT OF CHEWING CATTLE NUTS, that might be implicated. .....(oh my GOD...tss)

http://www.bseinquiry.gov.uk/files/yb/1993/08/12002001.pdf

Ministers will note from this that experts are of the view, that there is unlikely to be a direct link between the cases of BSE, and the occurance of CJD in the farmer.

(NOTE CJD increasing over 3 years. ...TSS)

http://www.bseinquiry.gov.uk/files/yb/1993/08/18004001.pdf

'AGE AT ONSET' is therefore likely to be a reflection of particulary aetiological factors, about which, for sporadic CJD at least, much is yet unknown. IT has therefore been suggested that examination of the f/d i/p of other groups with TSE's, and comparison with that of CJD subsets might help to elucidate aetiological mechanisms for sporadic CJD in particular; i.e. ALMOST A REVERSAL OF THE ORIGINAL UNDERTAKING.

http://www.bseinquiry.gov.uk/files/yb/1993/08/26001001.pdf

OCCUPATIONAL EXPOSURE TO BSE AND CJD

2. The Tyrrell Committee met on 7 October and the significance of the two cases of CJD reported in dairy farmers who had BSE-affected animals on their farms was discussed at some length, AS WERE THE IMPLICATIONS OF A THIRD (OR FORTH) similar case.

3. The Committee were unable to identify any possible risk factors over and above those that they had already considered, both in general and with particular of TASTING THE FEED does continue but there was no consensus about the value of advising farmers to discontinue this practice. Feed currently in use does not pose a risk because of the ruminant-ruminant feed ban.

http://www.bseinquiry.gov.uk/files/yb/1993/10/11001001.pdf

MRC

STRAIN CHARACTERISATION OF THE CREUTZFELDT-JAKOB DISEASE AGENT BY TRANSMISSION TO MICE

In view of the CONCERN that exposue to BSE OR SCRAPIE MAY POSE A RISK TO HUMANS, it is proposed investigate the relationship between sporadic creutzfeldt-jakob disease.....

http://www.bseinquiry.gov.uk/files/yb/1993/10/12001001.pdf

3. While Committee may have no leads to pursue on why farmers might be at increased risk, I hope they understand the urgency with which they will need to respond if or when a THIRD FARMER DEVELOPS CJD.

http://www.bseinquiry.gov.uk/files/yb/1993/10/18001001.pdf

CJD FARMERS WIFE 1989

http://www.bseinquiry.gov.uk/files/yb/1989/10/13007001.pdf

http://www.bseinquiry.gov.uk/files/yb/1989/10/13003001.pdf

cover-up of 4th farm worker ???

http://www.bseinquiry.gov.uk/files/yb/1995/10/23006001.pdf

http://www.bseinquiry.gov.uk/files/yb/1995/10/20006001.pdf

CONFIRMATION OF CJD IN FOURTH FARMER

http://www.bseinquiry.gov.uk/files/yb/1995/11/03008001.pdf

now story changes from;

SEAC concluded that, if the fourth case were confirmed, it would beworrying, especially as all four farmers with CJD would have had BSEcases on their farms.

to;

This is not unexpected...

was another farmer expected?

http://www.bseinquiry.gov.uk/files/yb/1995/11/13010001.pdf

4th farmer, and 1st teenager

http://www.bseinquiry.gov.uk/files/yb/1996/02/27003001.pdf

2. snip...

Over a 5 year period, which is the time period on which the advicefrom Professor Smith and Dr. Gore was based, and assuming apopulation of 120,000 dairy farm workers, and an annual incidenceof 1 per million cases of CJD in the general population, aDAIRY FARM WORKER IS 5 TIMES MORE LIKELY THANan individual in the general population to develop CJD. Using theactual current annual incidence of CJD in the UK of 0.7 permillion, this figure becomes 7.5 TIMES.

3. You will recall that the advice provided by Professor Smith in1993 and by Dr. Gore this month used the sub-population of dairyfarm workers who had had a case of BSE on their farms -63,000, which is approximately half the number of dairy farmworkers - as a denominator. If the above sums are repeated usingthis denominator population, taking an annual incidence in the generalpopulation of 1 per million the observed rate in this sub-populationis 10 TIMES, and taking an annual incidence of 0.7 per million,IT IS 15 TIMES (THE ''WORST CASE'' SCENARIO) thanthat in the general population...

http://www.bseinquiry.gov.uk/files/yb/1995/01/31004001.pdf

CJD YOUNG PEOPLE

in the USA, a 16 year old in 1978;

ALSO IN USA;

(20 year old died from sCJD in USA in 1980 and a 16 year old in 1981. see second url below)

in France, a 19 year old in 1982;

in Canada, a 14 year old of UK origin in 1988;

in Poland, cases in people aged 19, 23, and 27 were identified in a retrospective study (published 1991), having been originally misdiagnosed with a viral encephalitis;

Creutzfeldt's first patient in 1923 was aged 23.

http://www.bseinquiry.gov.uk/files/yb/1995/10/27013001.pdf

20 year old died from sCJD in USA in 1980 and a 16 year old in 1981. A 19 year old died from sCJD in France in 1985. There is no evidence of an iatrogenic cause for those cases....

http://www.bseinquiry.gov.uk/files/yb/1995/10/04004001.pdf

USA MAD COW STRAIN MORE VIRULENT TO HUMANS THAN UK STRAIN

18 January 2007 - Draft minutes of the SEAC 95 meeting (426 KB) held on 7December 2006 are now available.

snip...

64. A member noted that at the recent Neuroprion meeting, a study waspresented showing that in transgenic mice BSE passaged in sheep may be morevirulent and infectious to a wider range of species than bovine derived BSE.

Other work presented suggested that BSE and bovine amyloidotic spongiformencephalopathy (BASE) MAY BE RELATED. A mutation had been identified in theprion protein gene in an AMERICAN BASE CASE THAT WAS SIMILAR IN NATURE TO AMUTATION FOUND IN CASES OF SPORADIC CJD.

Bovine Amyloid Spongiform Encephalopathy (BASE) is an atypical BSE straindiscovered recently in Italy, and similar or different atypical BSE caseswere also reported in other countries. The infectivity and phenotypes ofthese atypical BSE strains in humans are unknown. In collaboration withPierluigi Gambetti, as well as Maria Caramelli and her co-workers, we haveinoculated transgenic mice expressing human prion protein with brainhomogenates from BASE or BSE infected cattle. Our data shows that about halfof the BASE-inoculated mice became infected with an average incubation timeof about 19 months; in contrast, none of the BSE-inoculated mice appear tobe infected after more than 2 years.

***These results indicate that BASE is transmissible to humans and suggest that BASE is more virulent thanclassical BSE in humans.***